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Management of women at high risk
of breast cancer
Anne C Armstrong,1 Gareth D Evans2 3
Department of Oncology, Christie
Hospital Manchester, Manchester,
Manchester Centre for Genomic
Medicine, Manchester Academic
Health Science Centre, University of
Manchester, Manchester, UK
Department of Genetic Medicine,
St Mary’s Hospital, Central
Manchester Foundation Trust,
Manchester, UK
Correspondence to: A C Armstrong
[email protected]
Cite this as: BMJ 2014;348:g2756
doi: 10.1136/bmj.g2756
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Breast cancer is the commonest malignancy diagnosed
in women worldwide and accounts for over 30% of all
cancers diagnosed in women in the United Kingdom.1
The average lifetime risk of developing breast cancer
for women in the United Kingdom and United States is
estimated to be 12%,1 although this may be an overestimate, as it is not clear what age this assumes a woman
lives to and whether full adjustment has been made for
those who die young from other causes. It is also unclear
whether multiple breast cancers in a single woman are
counted as several women with breast cancer.
The risk of breast cancer is multifactorial and is an
interaction between environmental, lifestyle, hormonal,
and genetic factors.2 3 Some women have a particularly
high risk of breast cancer owing to their family history, or,
less commonly, after supradiaphragmatic radiotherapy
for Hodgkin’s lymphoma. This review discusses how to
identify women who are at high risk of breast cancer as
a result of their family history or irradiation and outlines
the management options for such women, including surveillance and risk reducing strategies. A further group
of women diagnosed on the basis of a breast biopsy as
having atypical ductal or lobular hyperplasia are also at
increased risk of breast cancer; these women are not discussed further in this review.
When should a woman be considered at high risk of breast
A risk assessment for breast cancer is complex and no
consistent definition or threshold for high risk has been
established. Within UK practice, high risk, as defined by
the National Institute for Health and Care Excellence,4
is a lifetime risk of 30% or greater, which equates to a
more than 8% risk of breast cancer at age 40-50 years.
The high risk threshold used in the United Kingdom is
similar to that in other European countries, although in
North America the threshold for screening using magnetic resonance imaging is a lifetime risk of 20-25%.5
NICE guidelines have algorithms for identifying high risk
women, which include two close (first or second degree)
The risk of breast cancer is multifactorial, but some women will have a high risk because of a
genetic predisposition or, rarely, as a consequence of radiotherapy at a young age
Women with a family history suggestive of a genetic predisposition to cancer should be
referred to local genetics services for formal assessment
Annual magnetic resonance imaging and mammography (unless a carrier of the TP53 gene)
in high risk women identifies more breast cancers than does mammography alone
Risk reducing bilateral salpingo-oophorectomy and risk reducing mastectomy reduces the risk
of breast cancer by 50% and 90-95%, respectively, in carriers of BRCA1 and BRCA2 mutations
Chemoprevention with drugs such as tamoxifen for five years reduces the risk of breast
cancer by about 30% and can be a useful alternative to risk reducing surgery
We searched PubMed using search terms such as “breast
cancer risk” and “hereditary breast cancer.” Studies
included were those written in English, and included
case-control studies, randomised control trials, and
meta-analyses. We also consulted relevant national and
international guidelines, including those of the National
Institute for Health and Care Excellence, and we were
part of the NICE Guideline Development Group where all
relevant evidence was identified and summarised.
relatives with breast cancer with an average age of less
than 50, three with breast cancer aged less than 60, or
four with breast cancer at any age. These are “catch all”
criteria, which will not make all women who meet these
criteria fit the lifetime or 10 year risk criterion. Another
high risk criterion includes women with a family history
of both breast and ovarian cancer, which specifically
highlights the possibility of a BRCA1/2 mutation given
the increased risk of both cancers associated with mutations in these genes.
In most women with breast cancer the cause is
unknown. Those with breast cancer can be considered
at high risk if they meet the criteria mentioned above,
including their own breast cancer. Each close relative
with a diagnosis of breast cancer increases a woman’s risk
of developing breast cancer, especially with a diagnosis at
a young age (<50 years). Such families may have a genetic
predisposition to the development of breast cancer, with
about 5% of all breast cancers being attributable to inherited mutations in specific genes such as BRCA1, BRCA2,
and TP53. In any individual the genetic risk factors will
be modified by other risk factors.
In women of Ashkenazi Jewish descent a family history
of breast cancer poses a higher risk than in women of nonJewish descent because of the high prevalence and penetrance of BRCA1 and BRCA2 mutations (2.5%).6 In this
population any breast cancer is associated with a 10%
carrier rate of BRCA1/2, with higher rates for women with
a diagnosis at a younger age. Furthermore, three specific
“founder” mutations (two in BRCA1 and one in BRCA2)
have been identified within this population, making
genetic testing based on only these mutations a much
more sensitive and specific test.
It is also clear that women who received supra­
diaphragmatic radiotherapy at a young age as treatment
for Hodgkin’s lymphoma have a high risk of breast c­ancer,
which 20-40 years after treatment is nearly as high as
that of carriers of BRCA1/2.7 The peak risk is around age
14 years, which may be attributable to the accumulation of radiation damage in dividing cells d­uring breast
BMJ | 3 MAY 2014 | VOLUME 348
Table 1 | Breast cancer associated cancer predisposition syndromes and associated risk of breast cancer9
Disease gene
PTEN Cowden
Breast cancer
Breast cancer
Breast cancer
Breast cancer
Neurofibroma, glioma, breast cancer
Breast cancer, thyroid
Gastrointestinal malignancy, breast
Sarcoma, breast cancer (women), gliomas
Gastric, breast (women)
Breast/ovary (women), prostate (men), pancreas
Breast (women), ovary
Tumour age (years)
1st year, 1st year, >25
>25, 30
20, >25
1st year, >16, 1st year
>16, >35
>18, >30, >30
>18, >20
Table 2 | Referral criteria for family history and genetics clinics*4
Referral to family history clinics/secondary care
Referral to genetics clinics/tertiary care
One first degree relative with breast cancer at age
<40 years
One first degree male relative with breast cancer
at any age
Two first or second degree relatives with breast
cancer at any age
Two close relatives with breast cancer at any age
and a close relative with ovarian cancer
Three first or second degree relatives with breast
cancer at any age
Triple negative breast cancer at age <40 years
Three first or second degree relatives with breast
cancer at any age
Two first or second degree relatives with breast cancer at age
<50 years
Three first or second degree relatives at age <60 years with
breast cancer
Four first degree relatives with breast cancer at any age
Ovarian or male breast cancer at any age and on same side
of family and any of: one first or second degree relative aged
<50 years; two first or second degree relatives aged <60 years;
another ovarian cancer at any age
Any breast cancer and Jewish ancestry
*For bilateral breast cancer each breast cancer counts as one relative.
Which genes are implicated in a high risk of breast cancer?
Several genes are associated with a high risk of breast cancer. Of the known high risk genes, mutations in BRCA1 and
BRCA2 are the most common and account for about 20%
of the familial component. Germline mutations in other
high risk genes such as TP53, PTEN, and STK11 are less
common and identified in less than 1% of families with
breast cancer (table 1).8
Carriers of mutations in BRCA1 and BRCA2 have a high
lifetime risk of breast cancer (around 65-85% with BRCA1
and 40-85% with BRCA2)10‑12 as well as a high risk of ovarian cancer (40-60% with BRCA1 and 10-30% with BRCA2).
BRCA2 mutations also confer an excess risk of prostate
cancer, pancreatic cancer, and melanoma. The frequencies of BRCA1/BRCA2 mutations in breast cancer populations unselected for family history or age of diagnosis are,
however, low and account for about 2-3% of breast cancers
overall,13 but they are about 10% in founder populations
such as Ashkenazi Jewish.
Most breast cancers that arise in carriers of the BRCA1
mutation are “triple negative”—that is, the cancers lack
receptors for oestrogen, progesterone, and human epidermal growth factor receptor 2 (Her2).13 The immune phenotye
of cancers associated with BRCA2 mutations reflect that of
sporadic cancers, with most cancers expressing receptors for
oestrogen and progesterone with only 16% triple negative.14
When and how should a family history be taken?
Although 2004 guidelines from NICE did not advocate taking a family history proactively, much has changed in terms
of extra available surveillance and preventive options for
BMJ | 3 MAY 2014 | VOLUME 348
Risk (%)
100, 12, 17
60, 10
60, 40
80, 95, 20
70-80, 20-40
40-90, 20, 5
60-90, 40-60
Birth incidence of mutations
1 in 200
1 in 200
1 in 1000
<1 in 1000
1 in 2600
1 in 200 000-250 000
1 in 25 000
1 in 30 000
1 in 800
1 in 1000
Life expectancy
54-72 years
Reduced in women
58 years
Severely reduced
68 years
62 years
those women with at least moderate risk.15 Moderate risk
as defined by NICE is a lifetime risk of 17-29% or a 10 year
risk at age 40 of 3-7.9%. When risk is being assessed in
primary or secondary care, at least a two generation family history, including paternal relatives, should be taken
from women seeking advice. A family history of breast
cancer should also be sought in women aged more than
30 starting combined oral contraception and women aged
more than 50 starting combined hormone replacement
therapy. Women meeting at least moderate risk criteria (for
instance a mother or sister with breast cancer at age <40 or
two close relatives at any age) should be offered a referral
to secondary care (the local family history clinic or breast
clinic) but for women with a known family gene mutation,
direct referral to genetic services is appropriate (table 2).
In the United Kingdom, family history clinics are available
in most localities, with over 100 countrywide, but models
may differ in other countries. Nonetheless, much management of familial breast cancer does take place in secondary
care around the world, with surveillance organised by local
breast surgeons and gynaecologists.
When referred to a secondary care clinic, women will
have a preclinic questionnaire administered to assess eligibility or a family history elicited directly. Other non-genetic
risk factors such as pregnancy history and age at menarche
and menopause are also taken. The woman’s risk is
assessed usually by use of a risk algorithm such as TyrerCuzick16 or BOADICEA.17 If a woman is in the high risk category (lifetime risk ≥30%) or she or her affected relative has
a 10% or more chance of carrying a BRCA1/2 mutation she
will be offered referral to a tertiary care genetics service.
Extra surveillance will be offered as appropriate (table 3).
An assessment will also be made of others in the family
who may benefit from screening or genetic testing. Use of
a risk algorithm to assess the 10% threshold can be made
in family history clinics using a simple scoring system such
as the Manchester score18 or a computer algorithm such as
BOADICEA.17 Women from founder populations such as
Ashkenazi Jewish (carrier frequency 2.5%) and Icelandic
(0.5%) can be considered for BRCA1/2 testing with much
less significant family histories. Several algorithms may be
used in tertiary care. The figure shows an example of a risk
output from Tyer-Cuzick version 6. Fully comprehensive
algorithms such as Tyrer-Cuzick incorporate family history
with other known risk factors such as age at menarche and
menopause and at first full term pregnancy, overweight or
obesity, and breast biopsy information. Newer risk factors
Annual mammographic surveillance
Annual breast magnetic resonance imaging
No surveillance
Known or suspected BRCA1/BRCA2 mutation
Known or suspected BRCA1/BRCA2 mutation
Known or suspected BRCA1/BRCA2 mutation
Known or suspected BRCA1/BRCA2 mutation
TP53 carrier†
Known or suspected BRCA1/BRCA2/TP53 mutation
Known or suspected BRCA1/BRCA2/TP53 mutation
Known TP53 mutation
Known TP53 mutation
*For guidance on surveillance for women at moderate risk of breast cancer see National Institute for Health and Care
Excellence guidelines.4
†Mammographic surveillance is not recommended for TP53 carriers owing to risk of ionising radiation in this patient group.
such as mammographic density are being incorporated.
Efforts are under way internationally to target screening,
and preventive measures by proper risk stratification and
accurate risk assessments are vital to this aim.
Counselling includes advising women about their risk of
breast cancer and what they can do about it, as well as
the possibility of genetic testing. Although many genes
and genetic factors have been identified, currently there
is really only good utility in offering testing for women with
high risk genes and in particular mutations in BRCA1 and
BRCA2. Testing will usually start with the woman who has
breast or ovarian cancer to develop a definitive test for that
family. Women undergoing testing need to be aware of the
likelihood of testing positive for a mutation that causes
disease as well as for a variant of uncertain significance
(about 5% of BRCA1/2 tests find missense mutations, most
of which are thought to be harmless).
The decision to undergo presymptomatic testing for a
known BRCA1/2 mutation can involve complex emotions
and bring back memories of a relative’s diagnosis, treatment, and death. Many women do not choose to have
testing, and those that do may leave this for many years,
particularly if they are a young adult when first eligible. As
such most genetics centres see women at least twice before
taking a predictive sample. Women who are considering
being tested for a known family mutation or being considered for testing where no living relative is available will
need a full discussion of their risks for breast and ovarian
cancer, how these can be managed, and any effects on life
or health insurance dependent on where they live.
and is therefore recommended for the high risk population.
There are, however, concerns about exposing young women
to regular doses of ionising radiation. One study modelled
the risk of radiation induced cancers against reductions
in mortality from mammographic screening in carriers of
the BRCA mutation and suggested no net benefit of mammographic screening in women aged less than 30.20 NICE
advocate no mammography in women aged less than 30 with
a familial risk.2 Breast magnetic resonance imaging, with no
exposure to radiation, has a sensitivity of about 80% and
identifies more cancers in high risk women than does mammography (sensitivity 30-40%).21 22 Magnetic resonance
imaging is less specific, leading to additional imaging and
biopsies. In high risk women, surveillance with both magnetic resonance imaging and mammography is better than
either test alone.22 23
National2 and international guidelines recommend
enhanced screening for women with a very high risk of
familial breast cancer who have not had risk reducing
mastectomies (table 3). This includes annual surveillance
with magnetic resonance imaging from age 30-49 years for
women who have a known BRCA1, BRCA2, or TP53 mutation or are at a more than 30% probability of such and, for
BRCA1/2, annual mammography from the age of 40 to 69.
UK guidelines also recommend the use of annual mammography and magnetic resonance imaging in women who have
received supradiaphragmatic radiotherapy when less than
36, starting eight years after treatment.24
Woman aged 30 years
Age at menarch, 12 years
Age at first birth, 26 years
Person is premenopausal
Height, 5 ft 4 in (1.63 m)
Weight 9 stone (57.2 kg)
Never used hormone replacement therapy
Risk after 10 years, 10.26%
35 30
10 year population risk, 0.523%
Lifetime risk, 48.82%
Lifetime population risk, 10.21%
Probability of being a carrier of BRCA1 gene, 20.97%
Probability of being a carrier of BRCA2 gene, 22.55%
% at risk
Table 3 | Screening for women at high risk of breast cancer*4
45 38
Ov 67
Personal risk
Population risk
How are high risk women followed up?
Breast screening aims to diagnose cancer earlier to allow
timely therapeutic intervention that may consequently
be more effective than if left to later. In all women, breast
screening with mammography is predicted to reduce breast
cancer mortality,19 although controversy remains about the
absolute benefit of screening as well as the impact of overdiagnosis and overtreatment of screen detected low grade
and in situ breast cancers. In the United Kingdom, women
are offered screening from age 47-50 within the NHS breast
screening programme. Many similar screening programmes
exist across Europe and worldwide.
Mammographic screening of younger women is generally less effective than of older women because of increased
breast density. Digital mammography is more accurate than
film mammography in younger women with dense breasts
10 year risk
Tyrer-Cuzick readout of a woman (arrowed) at high risk of
breast cancer. The woman is eligible without genetic testing for
annual screening by magnetic resonance imaging aged 30-50
and for genetic testing. Her affected mother and aunt, if alive,
can be offered genetic testing for BRCA1/2 as they qualify
on all algorithms (Manchester score 30 is well above the 15
threshold for 10%). If they are not alive the proband and her
sister could have genetic testing as they have a >10% chance of
a BRCA1/2 mutation. The sister, now aged 35, could be offered
tamoxifen for five years
BMJ | 3 MAY 2014 | VOLUME 348
Healthcare professionals
National Institute for Health and Care Excellence.
Familial breast cancer: classification and care of people at risk of familial breast cancer and
management of breast cancer and related risks in people with a family history of breast
cancer. (Clinical guideline 164.) NICE, 2013—current UK guidance on the management of
patients at high risk of breast cancer due to their family history
Hilgart JS, Coles B, Iredale R. Cancer genetic risk assessment for individuals at risk of
familial breast cancer. Cochrane Database Syst Rev 2012;2:CD003721—assesses the
impact of risk assessment services on this group of patients
National Cancer Institute Cancer Topics
—information about breast cancer genetics, other risk factors, and breast cancer prevention
Breast Cancer Care
Cancer Research UK
Breast cancer surveillance is non-invasive, has few
adverse long term effects, and does not interfere with child
bearing. The risk of false positive results can lead to additional investigations, including imaging and biopsies, and
some women find magnetic resonance imaging unacceptably claustrophobic. Furthermore, magnetic resonance imaging does not prevent breast cancer and there is no evidence
as yet that breast screening reduces the risk of breast cancer
deaths in high risk women.
When is prophylactic surgery or chemoprevention
Risk reducing mastectomies
Women with high risk of breast cancer may decide to
undergo surgery to reduce their risk. Bilateral risk reducing
mastectomies remove most but not all breast tissue. Casecontrol studies in patients with BRCA1/2 mutations found
than surgery reduced the risk of breast cancer by 90-95%.25
Although randomised trials comparing the efficacy of bilateral risk reducing mastectomy with regular surveillance
would be an ethical challenge, prospective observational
studies have been published, with one study of more than
2000 years of patient observation finding 57 breast cancer
cases in the surveillance group compared with none in the
surgical group.26 Overall survival benefits from bilateral
risk reducing mastectomy alone have yet to be shown, but
one study reported that any form of risk reducing surgery
in women with BRCA1 or BRCA2 mutations improved
survival,27 and in two recent studies contralateral mastectomy has been shown to improve survival in women with
BRCA1/2 mutations.28 29
Bilateral risk reducing mastectomy is a major undertaking
for women, who need time to discuss their options and the
risks of each procedure, including the potential for ongoing
interventions such as surgical revisions and nipple tattooing. There is a small (about 2-5%) possibility of finding an
occult malignancy during risk reducing mastectomy, despite
preoperative screening investigations.26 Several studies have
evaluated the psychological impact of bilateral risk reducing mastectomies, which in general (but not universally)
BMJ | 3 MAY 2014 | VOLUME 348
Breast cancer in general is a multifactorial disease and only
about 5% of breast cancers are due to inherited mutations
in high risk genes such as BRCA1/2 and TP53
Genetic testing for high risk genes is performed only after
suitable counselling in family history clinics and with
informed consent
Does surveillance with magnetic resonance imaging
improve overall survival in patients at high risk of breast
What are the differences in clinical and psychological
outcomes in women who chose to have or chose not to
have risk reducing surgery?
Is chemoprevention effective in carriers of
BRCA1/2 mutations and in women who received
supradiaphragmatic radiotherapy at a young age?
Are aromatase inhibitors more effective than tamoxifen at
reducing the risk of breast cancer in women at high risk?
show good levels of satisfaction and reduced anxiety after
the procedure.30 31
Bilateral risk reducing salpingo-oophorectomy
Women who have inherited mutations of BRCA1 and BRCA2
may also undergo risk reducing bilateral salpingo-oophorectomy. This reduces the risk of ovarian and breast cancer;
a meta-analysis of all case series of the procedure suggesting that bilateral salpingo-oophorectomy performed before
natural menopause reduces the risk of breast cancer by up
to 50%.32 This is thought to be due to the reduction in circulating oestrogen. The benefits of risk reducing bilateral
salpingo-oophorectomy may be greater in carriers of the
BRCA2 mutation compared with BRCA1 mutation, which is
likely to relate to the greater frequency of oestrogen receptor
positive breast cancer in carriers of the BRCA2 mutation. Nevertheless, ongoing breast surveillance is still recommended
in these women and there are some prospective case series
that suggest the incidence of breast cancer after risk reducing
bilateral salpingo-oophorectomy is still high.33
The ideal age for risk reducing bilateral salpingooophorectomy remains uncertain, but studies suggesting
an earlier age of onset of cancers in carriers of the BRCA1
mutation support earlier intervention compared with carriers of the BRCA2 mutation. A surgical menopause can
result in acute symptoms and long term risks of oestrogen
deficiency. Although the use of hormone replacement therapy after natural menopause has been in decline since the
association between breast cancer and hormone replacement therapy use in the Million Womens Study,34 the use
of hormone replacement therapy for women with BRCA1
and BRCA2 mutations until the age of an expected menopause seems to be safe35 and is advised.4 Risk reducing
bilateral salpingo-oophorectomy at ages 38-40 for carriers
of the BRCA1 mutation and at ages 40-45 for carriers of the
BRCA2 mutation would seem to be a reasonable balance.
In women with a diagnosis of (an oestrogen receptor
positive) cancer, selective oestrogen receptor modulators,
such as tamoxifen and raloxifene, and aromatase inhibitors
reduce the risk of recurrence of that cancer as well as the risk
of a contralateral primary breast cancer. Such drugs have
therefore been investigated as preventive agents as an alternative to risk reducing surgery in women with a high risk of
breast cancer. Tamoxifen has efficacy in premenopausal and
postmenopasual women, whereas aromatase inhibitors are
only effective in postmenopausal women. Raloxifene only
has efficacy data in postmenopausal women.
A meta-analysis of randomised trials of selective oestrogen
receptor modulators for breast cancer prevention, with data
on 83 000 women, showed a 38% reduction in incidence
of oestrogen receptor positive (but not oestrogen receptor
negative) breast cancer with five years of treatment.36 The
absolute benefit of treatment depended on the absolute risk
of breast cancer, but overall this equated to a need to treat
42 women to prevent one cancer. Similar to the benefit of
adjuvant endocrine treatment for breast cancer, the benefits
of chemoprevention extend beyond the five years that the
drug is taken, with evidence of risk reduction extending to
at least five years after completion.
Other studies have investigated the use of the aromatase
inhibitors, exemestane and anastrozole, as chemopreventive
agents. The recently published IBIS-II study, in which 3864
postmenopausal women were randomly assigned to anastrazole 1 mg daily or to placebo, showed an enhanced risk
reduction with anastrazole treatment for five years compared
with the risk reduction seen in the studies using selective
oestrogen receptor modulators. After five years of follow-up
40 women in the anastrazole arm had developed breast cancer compared with 85 in the placebo arm (hazard ratio 0.47,
95% confidence interval 0.32 to 0.68).37 Selective oestrogen
receptor modulators and aromatase inhibitors have yet to be
compared head to head in the same study.
No study has as yet shown an overall survival advantage
from any chemopreventive strategy. Furthermore, from the
available evidence the drugs prevent the incidence of oestrogen receptor positive but not oestrogen receptor negative
cancers and may not be as effective in BRCA1 carriers where
triple negative cancers predominate. Chemoprevention can
be associated with potentially serious adverse events—for
example, tamoxifen causes a small excess risk of venous
thrombosis (around 4-7 events per 1000 women over five
years) and endometrial malignancy (around 4 excess cases
per 1000, with most of the excess risk in postmenopausal
women).38 Aromatase inhibitors (which are not currently
approved for chemoprevention by NICE) cause loss of bone
mineral density and an increased risk of osteoporosis. All
women starting treatment with an aromatase inhibitor
should have baseline bone mineral density monitoring
according to national guidelines.39
The uptake of chemoprevention worldwide is low despite
favourable national guidance by NICE (for tamoxifen and
raloxifene), the American Society of Clinical Oncology, and
other institutions. Possible explanations for this include
concerns about side effects of the drugs and a lack of awareness among women and healthcare providers.40 For women
at high risk of an oestrogen receptor positive breast cancer,
these drugs can be a useful option if they wish to avoid or
delay risk reducing surgery. The drugs are, however, less
effective than risk reducing surgery and have the potential
for serious adverse events. The potential benefits and risks
of these drugs require careful counselling and quantifying,
which may best be performed within secondary or tertiary
care settings. Decision aids are being developed to help
women make a decision regarding treatment with these
Competing interests: AA was an expert member of the NICE Familial Breast
Cancer Guideline Development Group (2013 update). GE was the chair of
the same group. GE and AA are coauthors of a manuscript in preparation.
Provenance and peer review: Commissioned; externally peer reviewed.
References are in the version on
ANSWERS TO ENDGAMES, p 38 For long answers go to the Education channel on
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B: Patellar tendon
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A man with a palpable abdominal mass
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